Peritoneal dialysis solutions and methods usable to minimize the injury and adverse physiological effects caused by peritonitis

ABSTRACT

Peritoneal dialysis solutions are specially formulated for use during and immediately after an episode of peritonitis. The solutions include one or more additives to minimize the injury and physiological effects that peritonitis can cause. One additive is a mixture of amino acids sufficient to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form. Another additive is a compound that scavenges free radicals generated by peritoneal macrophages activated by the peritonitis. Another additive is chondroitin sulfate that changes the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate. Another additive is the degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.

This is a division of application Ser. No. 08/077,815, filed on Jun. 15,1993, now U.S. Pat. No. 5,597,805 which is a continuation of Ser. No.07/830,721, filed on Feb. 4, 1992, now abandoned.

FIELD OF THE INVENTION

The invention generally relates to peritoneal dialysis solutions,especially those used in the practice of continuous ambulatoryperitoneal dialysis, or CAPD.

BACKGROUND OF THE INVENTION

Peritoneal dialysis periodically infuses sterile aqueous solution intothe peritoneal cavity. Diffusion exchange takes place between thesolution and the bloodstream across the natural body membranes. Thediffusion removes the waste products that the kidneys normally excrete.The waste products typically consist of solutes like sodium and chlorideions, and the other compounds normally excreted through the kidneys likeas urea, creatinine, and water. The diffusion of water across theperitoneal membrane during dialysis is called ultrafiltration.

The inflammation of the peritoneum, called peritonitis, is an undesiredcomplication of peritoneal dialysis. The inflammation may lead to lossof mesothelial cells and the excessive growth of fibrous connectivetissue in the peritoneum membrane, called fibrosis. These reactions canlead to the loss of ultrafiltration during dialysis.

In addition, peritonitis may lead to increased protein loss in thepatient, with the patient not feeling well enough to eat to replace thisloss.

To make up for the reduction in normal ultrafiltration rates, peritonealdialysis patients experiencing peritonitis often receive hypertonicdialysis solutions, typically containing glucose as an osmotic solute.However, the use of hypertonic solutions for these purposes may becounterproductive. Due to their low pH, high osmolarity, and thepresence of glucose, the solutions may inhibit the necessaryregeneration of mesothelial cells. They also may lead to the growth offibroblasts, causing fibrosis.

To enhance the patient's anabolic state and replace protein lossexperienced during peritonitis, conventional dialysis solutions also mayinclude mixtures of nutritionally essential amino acids (likemethionine, tryptophan, and isoleucine) and nutritionally non-essentialamino acids (like glycine and alanine). However, the presence of theseamino acids may be counterproductive, too. Many of these amino acids caninhibit the proliferation of mesothelial cells.

Therefore, there is a need for peritoneal dialysis solutions that can beused during and immediately after peritonitis without potentiallycounterproductive effects. The solutions would promote the replacementof mesothelial cells, minimize the formation of fibroblasts, and counterthe attendant loss of ultrafiltration that peritonitis often causes.

SUMMARY OF THE INVENTION

The invention provides improved peritoneal dialysis solutions that canbe used during and after episodes of peritonitis to protect the patientagainst the inflammatory reactions of peritonitis, fibrosis, and theloss of ultrafiltration. The invention also provides improved peritonealdialysis solutions that can be used after episodes of peritonitis to atleast partially restore ultrafiltration characteristics lost due toperitonitis.

One aspect of the invention provides peritoneal dialysis solutions thatmaintain a positive nitrogen balance during peritonitis withoutsignificantly inhibiting the proliferation of mesothelial cells. Thisaspect of the invention replaces at least some individual amino acids inthe dialysis solution with amino acids in their dipeptide form.

The inventors have discovered that certain amino acids stunt theproliferation of mesothelial cells. By using these amino acids in theirdipeptide form instead, significant improvements in the proliferation ofmesothelial cells occur. In a preferred embodiment, at least some aminoacids like methionine, tryptophan, or isoleucine appear in theirdipeptide form (for example, glycine-tryptophan) to achieve thisbeneficial effect.

The inclusion in a peritoneal dialysis solution of amino acids indipeptide form with other essential and non-essential amino acidsenhances the anabolic state of the patient suffering peritonitis. Inaddition, the solution does not unduly inhibit the regeneration ofmesothelial cells that is necessary to the patient's healing process.

Another aspect of the invention supplements peritoneal dialysis solutionwith compounds that act as scavengers of free radicals present withinthe peritoneal cavity. The inventors have discovered that the freeradicals released by peritoneal cells during peritonitis can injuremesothelial and endothelial cells and may otherwise case disfunction ofthe peritoneal membrane. The presence in a peritoneal dialysis solutionof compounds that scavenge these free radicals decreases the injury thatthe peritoneum might otherwise suffer during peritonitis. In a preferredembodiment, the scavengers are vitamin E, procysteine, superoxidedismutase, or chondroitin sulfate.

The inventors have also discovered that use of a dialysis solutioncontaining chondroitin sulfate also beneficially changes thepermeability of the peritoneal membrane during subsequent dialysis usingconventional solutions. Chondroitin sulfate enhances the subsequentultrafiltration characteristics of the peritoneal membrane usingconventional dialysis solution. It also decreases the absorption ofglucose and transperitoneal loss of proteins with no change in ureadiffusion. Chondroitin sulfate therefore serves not only as a freeradical scavenger to minimize cellular injury caused by inflammationduring peritonitis, but it can be used after an episode of peritonitisto at least partially restore loss of ultrafiltration characteristicscaused by peritonitis.

Another aspect of the invention includes the degradation products ofhyaluronic acid as an additive to a peritoneal dialysis solution toenhance the regeneration of the peritoneal mesothelium without fibrosis.The inventors believe that these degradation products, principallyoligosaccarides, will increase the proliferation of endothelial cellswithout affecting fibroblasts growth.

Used alone or in combination, these additive compounds make possible theformulation of peritoneal dialysis solutions specifically tailored foruse during and immediately after the development of peritonitis.

These additive compounds, used alone or in combination in peritonealdialysis solutions, can enhance the regeneration of mesothelial cellsand prevent the growth of fibroblasts. They can improve the nutritionalstatus of the patient during peritonitis. They can actively decrease thedegree of damage occurring during inflammation of the peritonealmembrane. They can restore the peritoneal membrane to itspre-peritonitis condition.

The many features and the advantages of the invention will become evenmore apparent after reading the following detailed description,associated drawings, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing the mean value in ⁸⁶ Rb uptake by humanmesothelial cells (HMC) through different pathways after being culturedfor 7 days in medium with high concentrations (90 mM) of glucose,glycerol, and mannitol, expressed as a % of control where the HMC werecultured in normotonic medium; and

FIG. 2 is a graph showing the accumulation of ⁸⁶ Rb during 72 hours inHMC exposed to different high glucose concentrations, expressed as a %of control where the HMC were cultured in normotonic medium.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

After an episode of peritonitis, the CAPD patient typically receives ahypertonic peritoneal dialysis solution containing glucose. The intentis to counteract the loss of ultrafiltration that frequently occursduring peritonitis.

However, hypertonic peritoneal dialysis solutions with glucose mayactually interfere with the regeneration of mesothelial cells andthereby interfere with the patient's recovery from the inflammatoryeffects of peritonitis. Such solutions also may encourage the growthfibroblasts and could contribute to peritoneal fibrosis.

The inventors have experimentally determined that potassium (measuredwith its analog ⁸⁶ Rb) enters human mesothelial cells (HMC) throughthree different pathways:

(1) through an active channel that the glucoside ouabain blocks in adose dependent way, which corresponds to the activity of the Na-K-ATPasepump in plasmalemma;

(2) through another active channel that the diuretic drug furosemideblocks in a dose dependent way, but that is not blocked by ouabain; and

(3) through a passive channel that neither ouabain or furosemide block.

The inventors have also experimentally determined that about 60% of ⁸⁶Rb transport occurs through Active Channel (1), the Na-K-ATPase pump;about 29% through active Channel (2); and about 11% through passiveChannel (3).

As the following Example demonstrates, exposure of HMC to hyperosmolalmedium modifies the transport of ⁸⁶ Rb into the cells through all threepathways.

EXAMPLE 1

This study evaluated the mechanisms regulating transport of potassiumfrom the extracellular space into HMC in in vitro culture.

HMC were isolated from omentum following the method described in VanBronswwijk et al., "Cytotoxic Effects of Commercial ContinuousAmbulatory Peritoneal Dialysis (CAPD) Fluids and of BacterialExoproducts on Human Mesothelial Cells in Vitro," Perit Dial Intern,1989 (9): 197-202.

The HMC were seeded into 75 cm² culture flasks and grown to confluency.Then, the HMC were harvested with trypsin-EDTA solution and seeded into96-well culture plates and there again grown to confluency. The studyused the confluent mesothelial monolayers cultured in the 96-wellplates.

HMC were incubated in the culture medium for 7 days with various osmoticsolutions (90 mM and more of glucose or glycerol or mannitol). Afterincubation, potassium analog ⁸⁶ Rb was added to the medium. The uptakeof ⁸⁶ Rb by HMC was measured and compared with the uptake in control HMCnot exposed to osmotic solutes (the control HMC having been cultured ina normotonic medium).

As FIG. 1 shows, transport through the passive Channel (3) increases inHMC exposed chronically (over 7 days) to high concentration of all theosmotic solutes (90 mM). Mannitol also stimulated active transportthrough Channel (1), but glucose and glycerol both decreased Channel (1)transport. All solutes decreased active transport through Channel (2) aswell.

As FIG. 2 shows, the intracellular accumulation of ⁸⁶ Rb in HMC exposedfor 72 hours to increased concentrations of glucose diminishedproportionally to the glucose concentration, compared to theaccumulation in the control HMC.

The study demonstrates that chronic exposure of HMC to high glucoseconcentration (90 mM) decreases the activity of the Na-K-ATPase pump(i.e., Channel (1)), which is the main pump responsible forintracellular potassium accumulation. The activity of Channel (2) alsodecreases as a result to exposure of HMC to high glucose concentration.

In effect, this decreased capacity of HMC to take up potassium resultsin diminished accumulation of potassium in HMC. This may, in turn, causecellular disfunction like those associated with diabetic disordersresulting from reduced Na-K-ATPase activity. See Greene et al.,"Sorbitol, Phosphoinodsitides and Sodium--Potassium--ATPase in thePathogenesis of Diabetic Complications," N Engl J Med 1987; 316:599-606; and Yorek et al., "The Effect of Increased Glucose Levels onNa-K Pump Activity in Cultured Neuroblastoma Cells," J Neurochem 1988;51:605-610. HMC potassium depletion also may produce severe metabolicabnormalities such as deranged protein synthesis. See Lubin,"Intracellular Potassium and Control of Protein Synthesis," Fed Proc1964; 23: 994-997.

High concentration of glycerol, but not mannitol, produces the sameeffect as glucose. This suggests that the decrease in Na-K-ATPase pumpactivity depends upon the metabolism of the osmotic solute inside thecell, since both mannitol influx and metabolism in HMC are probablysmall.

The study also shows that chronic exposure of HMC to all osmotic solutesincreases the passive permeability (via Channel (3)) of the plasmalemmato ⁸⁶ Rb. This may be due to a "washout" of structural components of theplasmalemma, causing increased leakage and loss of intracellularmetabolic substrates. This, too, can lead to cellular disfunction.

Thus, increased extracellular tonicity due to high glucose concentrationmay cause HMC potassium loss both through diminished active influx,mostly by reduced Na-K-ATPase activity, and through an outflux ofion-rich water ("wash-out") from the cells due to a negative osmoticgradient. Also see Moreno et al., "Increase in Serum Potassium Resultingfrom the Administration of Hypertonic Mannitol and Other Solutions," JLab Clin Med 1969; 73: 291-294.

The presence of these disfunctions does not promote the regeneration ofmesothelial cells necessary to the healing process during and after aperitonitis episode.

The peritoneal dialysis solutions that embody the features of theinvention are specially formulated for patients for use during andimmediately after episodes of peritonitis. The solutions promote thehealing process to avoid or at least minimize the injury and adversephysiological effects of peritonitis upon the dialysis regime of thepatient.

Like conventional peritoneal dialysis solutions, the solutions thatembody the features of the invention include:

(1) physiological salts such as sodium chloride, calcium chloride andsodium acetate in appropriate concentrations to maintain a normalelectrolyte profile. Typical concentrations are from 116 to 140mEq/liter of sodium; 0 to 6 mEq/liter of calcium, and 100 to 144mEq/liter of chloride.

(2) lactate or bicarbonate in appropriate concentrations to maintain aphysiologically tolerable pH of between about 5 to about 7.4. Typicalconcentrations are from 30 to 45 mEq/liter of lactate; and

(3) glycerol or glucose polymers at a concentration (at least 0.5percent by weight) sufficient to generate the necessary osmotic pressureto remove water from the patient through ultrafiltration.

According to the invention, the solutions contain one or more of thefollowing additives:

(4) a mixture of essential and non-essential amino acids to serve as asource of supplemental nitrogen for the support of protein synthesis forthe patient and to counterbalance the protein that the patient losesbecause of peritonitis. According to this aspect of the invention, atleast some of these amino acids are present in their dipeptide form topromote the proliferation of mesothelial cells lost during peritonitis.

(5) a compound that scavenges free radicals produced by peritoneal cellsthat causes peroxidation of the peritoneum;

(6) chondroitin sulphate to restore at least a portion oftransperitoneal transport lost due to peritonitis;

(7) compounds consisting of the degradation products of hyaluronic acidto enhance the regeneration of the peritoneal mesothelium withoutfibrosis.

The following sections describe the benefits associated with eachAdditive (4) to (7).

AMINO ACID ADDITIVE (4)

A preferred embodiment of the amino acid additive (4) comprises, basedon one liter of solution, about 0.1 to 10 mM each of the nutritionallyessential amino acids methionine, tryptophan, isoleucine, valine,leucine, lysine, histidine, threonine, and phenylalanine, at least someof which are present in their dipeptide form. When present asdipeptides, these amino acids do not inhibit mesothelial cellproliferation as much as they do when present as individual amino acids.

The most preferred embodiment includes at least tryptophan in itsdipeptide form (glycine-tryptophan, or gly-trp), as the individual aminoacid tryptophan inhibits mesothelial cell proliferation more than another individual amino acid.

The mixture also includes about 0.1 to 10 mM each of arginine, alanine,proline, glycine, serine, tyrosine, cysteine (cystine), and otherindividual, nutritionally non-essential amino acids as required tomaintain a positive nitrogen balance in the patient.

The following Example illustrates the benefits of using amino acids in adialysis solution, of which certain are in their dipeptide form.

EXAMPLE 2

This study evaluated the toxicity of a mixture of essential andnon-essential amino acids on the proliferation of HMC in conditionssimulating peritoneal dialysis.

HMC prepared as described in Example 1 were exposed to essential andnonessential amino acids. Adverse effects were measured in terms of theimpact upon cell proliferation (as measured by incorporation of3H-thymidine) and the release of LDH from cell cytoplasm.

All the amino acids evaluated inhibited the proliferation of HMC whenpresent. Tryptophan exhibited the most inhibition effect.

When HMC are exposed to tryptophan in a concentration of 5 nM for 24hours, their proliferation is reduced by 82%, compared to theproliferation of control HMC cells not exposed to tryptophan. After 24hours of exposure, tryptophan (5 mM) also increased the leakage of LDHfrom the mesothelial monolayer HMC by 740%, compared to the control HMCcells.

In contrast, after 24 hours of exposure to dipeptide tryptophan(gly-trp) in concentration of 5 mM, proliferation of HMC decreased byonly 30% and LDH release increased by only 180%, compared to the controlHMC cells.

In another experiment, growing HMC were exposed to two mixtures eachhaving a high concentration of amino acids (1.1%). One amino acidmixture contained tryptophan. The other amino acid mixture containedgly-trp instead of tryptophan. The concentration of both amino acidmixtures was progressively decreased by dilution down to 0.22% in 6hours. The HMC were incubated for 18 additional hours in media with thelow (0.22%) concentration.

The mixture of amino acids containing tryptophan reduced 3H-thymidineincorporation by 30%, compared to the control HMC not exposed to anyamino acid mixture. The mixture of amino acids in which the gly-trpreplaced the tryptophan reduced 3H-thymidine incorporation by only 17%.The inclusion of the dipeptide form of the amino acid in the mixturereduced the undesired effect by about 50%.

FREE RADICALS SCAVENGER ADDITIVE (5)

Peritonitis activates peritoneal macrophages (as proved by others). Theactivation of the macrophages leads to the increased generation of freeradicals. The inventors believe that the increased generation of freeradicals causes peritoneal peroxidation.

According to this aspect of the invention, the use of compounds thatscavenge free radicals in peritoneal dialysis solutions minimizes oralleviates peritoneal peroxidation during episodes of peritonitis.

The inventors have also shown that the increased presence of freeradicals also injures mesothelial cells in the peritoneum. The freeradicals probably also injure endothelial cells, too. The free radicalscan depolymerize hyaluronic acid and/or collagen in interstitium,causing disfunction of the peritoneal membrane.

According to this aspect of the invention, these undesired effects ofperitonitis also can be minimized or lessened by supplementing thedialysis solution with free radical scavengers.

EXAMPLE 3

In one experiment, exposure to normal saline in the peritoneal cavitiesof rats for over 6 days increased peroxidation of the peritonealmembrane, as measured by the concentration of malondialdehyde in theanimal's omentum: 8.12+/-0.51 uM/100 ug tissue (n=7) in controls notinfused with saline, compared to 11.36+/-1.07 uM/100 ug tissue (n=12) inrats infused with saline. In another experiment, one group of rats(n=22) was infused over 6 days with saline supplemented with vitamin E(0.1 g %). Another control group of rats (n=18) was infused over 6 dayswith saline alone. In rats infused with the vitamin E-supplementedsaline, the concentration of malondialdehyde in the omentum (andtherefore the severity of peritoneal peroxidation) was lower(4.53+/-0.30 uM/100 ug tissue) than in the rats infused with salinealone (9.38+/-0.90 uM/100 ug tissue).

In other in vitro experiments, free radicals generated by anxanthine-xanthine oxidase system were observed to injure mesothelialcells. The injury was prevented by using vitamin E (0.1% to 1.0%) andchondroitin sulphate (0.1%).

In another experiment, the xanthine-xanthine oxidase system was added todialysis solution (2.5% dextrose). The solution was infused into theperitoneal cavities of rats. The increased presence of the free radicalsgenerated by the infused oxidase system caused loss of ultrafiltrationand increased glucose absorption, the same physiological effectsobserved during episodes of peritonitis. This result further links theincreased presence of free radicals to the inflammatory effects andinjury of peritonitis.

The addition of free radical scavenger vitamin E (0.01%) reduced ortotally reversed the adverse effects caused by the free radicalsgenerated by the xanthine-xanthine oxidase system. The free radicalscavenger would have the same beneficial effect in the increasedpresence of the free radicals during peritonitis.

In a preferred embodiment, the scavengers are selected from the groupconsisting of vitamin E, procysteine, superoxide dismutase, andchondroitin sulfate and are present in concentrations of about 0.01 to0.5 g %.

TRANSPORT RESTORATION ADDITIVE (6)

Peritonitis can adversely alter peritoneal transport, leading to areduction of ultrafiltration. According to this aspect of the invention,the peritoneal dialysis solution includes chondroitin sulphate to changeor restore transperitoneal transport after an episode of peritonitis.

EXAMPLE 4

Saline supplemented with chondroitin sulphate (0.1 g %) was infused intothe peritoneal cavity of rats over a period of six days. Then,conventional 2.5% Dianeal peritoneal dialysis solution (sold by BaxterHealthcare Corporation, Deerfield, Ill.) was infused into the peritonealcavities of the rats.

The chronic exposure to the chondroitin sulphate modified thepermeability of the peritoneal membrane during the subsequent dialysiswith conventional dialysis solution. The net ultrafiltration measuredafter a dwell period of four hours was more than the ultrafiltrationmeasured before exposure to the chondroitin sulphate. Also, absorptionof glucose from the dialysate and transperitoneal loss of proteinsdecreased, with no change in urea diffusion, when compared to these sametransport parameters measured-before chronic exposure to the chondroitinsulphate.

This Example illustrates the benefits of using chondroitin sulphate in adialysis solution to restore transperitoneal transport after an episodeof peritonitis.

In a preferred embodiment, the chondroitin sulphate is present in aconcentration of about 0.01 to 0.5 g %.

REGENERATION ADDITIVE (7)

Wound healing during fetal life is characterized by healing withoutfibrosis or scar formation. It is believed that this healing process isat least partly mediated by the high concentration of hyaluronic acid ina fetal wound extramural matrix. By increasing the concentrations ofhyaluronic acid in the extracellular fluids of adults, the healing ofwounds without fibrosis is enhanced.

Other studies have shown that the hyaluronic acid is not responsible byitself. It is believed that its degradation products (oligosaccharides)that are the active agents in promoting fibrosis-free wound healing. Inin vitro experiments, oligosaccharides products of the degradation ofhyaluronic acid increase the proliferation of endothelial cells withouteffect on fibroblasts growth.

According to this aspect of the invention, peritoneal dialysis solutionincludes degradation products of hyaluronic acid to enhance theregeneration of the peritoneal mesothelium without fibrosis.

The dialysis solutions containing one or more of the additives (4) to(7), when sterile, may be used as the peritoneal dialysis solution in aconventional CAPD procedure, using the techniques and equipmentdeveloped and sold by the Baxter Healthcare Corporation, Deerfield, Ill.

The above description and Examples are for illustrative purposes only.They are not intended to limit the scope of the inventions, as definedin the following claims.

We claim:
 1. A peritoneal dialysis solution comprisingphysiologicalsalts in concentrations sufficient to affect the removal of solutes bydiffusion from the patient's blood across the peritoneal membrane intothe solution, the solution also including chondroitin sulfate to changethe permeability of the peritoneal membrane, and at least one compoundselected from the group consisting of vitamin E, procysteine, andsuperoxide dismutase to scavenge free radicals generated by activatedperitoneal macrophages during peritonitis.
 2. A solution according toclaim 1wherein the compound is present in a concentration of about 0.1 %to about 1%.
 3. A solution according to claim 1 and further includinganosmotic solute in concentrations sufficient to create an osmoticpressure to effect the removal of water by diffusion from the patient'sblood across the peritoneal membrane into the solution.
 4. A solutionaccording to claim 3wherein the osmotic solute includes a polymercomprising monomeric units selected from the group consisting of glucoseand glycerol.
 5. A peritoneal dialysis solution comprisingphysiologicalsalts in concentrations sufficient to affect the removal of solutes bydiffusion from the patient's blood across the peritoneal membrane intothe solution, and the degradation oligosaccharide products of hyaluronicacid to enhance the regeneration of the peritoneal mesothelium withoutfibrosis.
 6. A solution according to claim 5 and further includinganosmotic solute in concentrations sufficient to create an osmoticpressure to effect the removal of water by diffusion from the patient'sblood across the peritoneal membrane into the solution.
 7. A solutionaccording to claim 6wherein the osmotic solute includes a polymercomprising monomeric units selected from the group consisting of glucoseand glycerol.
 8. A peritoneal dialysis solution for use during anepisode of peritonitis comprisingphysiological salts in concentrationssufficient to affect the removal of solutes by diffusion from thepatient's blood across the peritoneal membrane into the solution; and atleast two additive compounds selected from the group consisting ofamixture of amino acids sufficient to maintain a positive nitrogenbalance, at least one of the amino acids being present in a dipeptideform, at least one scavenger compound selected from the group consistingof vitamin E, procysteine, and superoxide dismutase to scavenge freeradicals generated by activated peritoneal macrophages duringperitonitis, and oligosaccharide products of the degradation ofhyaluronic acid to enhance the regeneration of the peritonealmesothelium without fibrosis.
 9. A solution according to claim 8 andfurther including an osmotic solute in concentrations sufficient tocreate an osmotic pressure to effect the removal of water by diffusionfrom the patient's blood across the peritoneal membrane into thesolution.
 10. A solution according to claim 8wherein the mixture ofamino acids includes at least one amino acid selected from the groupconsisting of arginine, alanine, proline, glycine, serine, tyrosine, andcysteine (cystine).
 11. A solution according to claim 8 or 9wherein themixture of amino acids includes at least one amino acid selected fromthe group consisting of valine, leucine, lysine, isoleucine, methionine,histidine, threonine, tryptophan, and phenylalanine, at least one of theselected amino acid being in its dipeptide form.
 12. A solutionaccording to claim 11wherein the amino acid tryptophan is in itsdipeptide form.
 13. A solution according to claim 11wherein the aminoacid in dipeptide form is present in a concentration of about 2 mM toabout 10 mM, based upon one liter of solution.
 14. A solution accordingto claim 8wherein the scavenger is present in a concentration of about0.1% to about 1%.
 15. A method of performing peritoneal dialysis afterthe onset of peritonitis comprising the steps ofintroducing into theperitoneal cavity of a patient experiencing peritonitis a solutioncontaining physiological salts in concentrations sufficient to effectthe removal of solutes by diffusion from the patient's blood across theperitoneal membrane into the solution, and introducing into theperitoneal cavity at least one additional additive selected from thegroup consisting ofa mixture of amino acids sufficient to maintain apositive nitrogen balance, at least one of the amino acids being presentin a dipeptide form, at least one compound that scavenges free radicalsgenerated by peritoneal macrophages activated by the peritonitis,chondroitin sulfate in a concentration sufficient to change thepermeability of the peritoneal membrane during subsequent dialysis usingsolutions free of chondroitin sulfate, and the degradationoligosaccharide products of hyaluronic acid to enhance the regenerationof the peritoneal mesothelium without fibrosis.
 16. A method ofperforming peritoneal dialysis after the onset of peritonitis comprisingthe steps ofintroducing into the peritoneal cavity of a patientexperiencing peritonitis a solution containing physiological salts inconcentrations sufficient to effect the removal of solutes by diffusionfrom the patient's blood across the peritoneal membrane into thesolution, and maintaining a positive nitrogen balance in the patientwhile promoting the regeneration of mesothelial cells by introducinginto the peritoneal cavity a mixture of amino acids, at least one of theamino acids being present in a dipeptide form.
 17. A method ofperforming peritoneal dialysis after the onset of peritonitis comprisingthe steps ofintroducing into the peritoneal cavity of a patientexperiencing peritonitis a solution containing physiological salts inconcentrations sufficient to effect the removal of solutes by diffusionfrom the patient's blood across the peritoneal membrane into thesolution, and preventing injury to mesothelial cells by introducing intothe peritoneal cavity at least one compound that scavenges free radicalsgenerated by peritoneal macrophages activated by the peritonitis.
 18. Amethod of performing peritoneal dialysis after an episode of peritonitiscomprising the steps ofintroducing into the peritoneal cavity of apatient experiencing peritonitis a solution containing physiologicalsalts in concentrations sufficient to effect the removal of solutes bydiffusion from the patient's blood across the peritoneal membrane intothe solution, the solution also including chondroitin sulfate to changethe permeability of the peritoneal membrane, and at a later time, afterthe patient's peritonitis is over, introducing into the peritonealcavity of the patient a solution containing physiological salts inconcentrations sufficient to effect the removal of solutes by diffusionfrom the patient's blood across the peritoneal membrane, the solutionbeing free of chondroitin sulfate.
 19. A method of performing peritonealdialysis after an episode of peritonitis comprising the stepsofintroducing into the peritoneal cavity of a patient a solutioncontaining physiological salts in concentrations sufficient to effectthe removal of solutes by diffusion from the patient's blood across theperitoneal membrane into the solution, and introducing the degradationoligosaccharide products of hyaluronic acid into the peritoneal cavityto enhance the regeneration of the peritoneal mesothelium withoutfibrosis.
 20. A peritoneal dialysis solution comprisingphysiologicalsalts in concentrations sufficient to affect the removal of solutes bydiffusion from the patient's blood across the peritoneal membrane intothe solution, and at least one of procysteine or superoxide dismutase orboth to scavenge free radicals generated by activated peritonealmacrophages during peritonitis.
 21. A solution according to claim 20wherein the solution further comprises chondroitin sulfate.
 22. Aperitoneal dialysis solution for use during an episode of peritonitiscomprisingphysiological salts in concentrations sufficient to affect theremoval of solutes by diffusion from the patient's blood across theperitoneal membrane into the solution; and at least one additivecompound selected from the group consisting of a mixture of amino acidssufficient to maintain a positive nitrogen balance, at least one of theamino acids being present in a dipeptide form, at least one scavengercompound selected from the group consisting of procysteine andsuperoxide dismutase and mixtures thereof to scavenge free radicalsgenerated by activated peritoneal macrophages during peritonitis, andoligosaccharide products of the degradation of hyaluronic acid toenhance the regeneration of the peritoneal mesothelium without fibrosis.